Results from clinicopathological studies of amnesic patients and from studies of lesion-induced memory impairments in experimental animals provide convincing evidence that the hippocampal formation is essential for normal memory function. Dysfunction of the hippocampal formation following direct surgical ablation, cerebral ischemia or neurodegenerative conditions such as Alzheimer's disease, results in a profound impairment of memory characterized by an enduring inability to recreate a record of day-to-day events even though most past memories remain intact. The hippocampal formation thus appears to be essential for the formation of new memories but is not the sole or final repository of stored memories. The overall objective of the proposed program of neuroanatomical studies is to define the neural circuitry by which the hippocampal formation mediates its role in memory. Recent anatomical and behavioral data indicate that the perirhinal and parahippocampal cortices of the primate temporal lobe form the major interface for transfer of information between the hippocampal formation and the neocortex. A primary goal of the proposed studies will be to undertake a comprehensive analysis of the cytoarchitectonic organization and connectivity of the perirhinal and parahippocampal cortices. Damage to the diencephalon in human patients and experimental animals results in a severe memory impairment much like that observed after hippocampal damage. But transection of the major fiber connection between these two areas, the fornix, results in only a minor and transitory impairment. A second goal of the proposed studies is to use the lectin anterograde tracer PHA-L to determine the pathways and patterns of termination of diencephalic and other subcortical projections to the hippocampal formation. We will determine whether there are alternate routes through which the diencephalic and temporal lobe memory systems are linked. Behavioral and physiological studies in the rat hippocampus have made major advances in unraveling the mechanisms by which the hippocampus consolidates memory. These efforts, as well as computational approaches to hippocampal function, are dependent on precise and quantitative summaries of hippocampal neural circuitry. Proposed studies conducted in the rat will use the lectin tracer PHA-L to precisely define the topographic organization of intrinsic hippocampal connections. The extent of connectivity between hippocampal regions will be quantified using a recently developed image analysis procedure that relies on the increased axial resolution of the confocal laser microscope. Intracellular staining and three-dimensional reconstruction of single hippocampal neurons will provide quantitative information concerning the number and distribution of inputs to individual hippocampal neurons. Taken together, these studies should foster the development of a quantitative,, functional neuroanatomy of the hippocampal formation.